US3821384A - Pharmaceutical compositions containing a4-aryl-2-(3-pyridyl)thiazole and methods of using same - Google Patents

Pharmaceutical compositions containing a4-aryl-2-(3-pyridyl)thiazole and methods of using same Download PDF

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Publication number
US3821384A
US3821384A US00295501A US29550172A US3821384A US 3821384 A US3821384 A US 3821384A US 00295501 A US00295501 A US 00295501A US 29550172 A US29550172 A US 29550172A US 3821384 A US3821384 A US 3821384A
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dosage form
composition
pyridyl
compound
administrable dosage
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Inventor
Z Ariyan
W Harrison
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Uniroyal Chemical Co Inc
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Uniroyal Ltd Great Britain
Uniroyal Inc
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Priority to US00295501A priority Critical patent/US3821384A/en
Priority to DE19732350222 priority patent/DE2350222A1/de
Priority to GB4654973A priority patent/GB1451212A/en
Priority to FR7335757A priority patent/FR2208660B1/fr
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Assigned to UNIROYAL CHEMICAL COMPANY, INC., WORLD HEADQUARTERS, MIDDLEBURY, CT. 06749, A CORP. OF NEW JERSEY reassignment UNIROYAL CHEMICAL COMPANY, INC., WORLD HEADQUARTERS, MIDDLEBURY, CT. 06749, A CORP. OF NEW JERSEY ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: UNIROYAL, INC., A NEW YORK CORP.
Assigned to UNIROYAL CHEMICAL COMPANY, INC. reassignment UNIROYAL CHEMICAL COMPANY, INC. ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: UNIROYAL, INC., A NJ CORP.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame

Definitions

  • Certain 4-aryl-2-(3-pyridyl)thiazoles are useful as active agents for the central nervous system, e.g., possess anti-anxiety properties.
  • the invention is a method of reducing anxiety.
  • the invention is directed to pharamaceutical compositions comprising certain 4- aryl-2-(3-pyridyl)-thiazoles.
  • a further aspect relates to the use of certain of said thiazoles to induce a hypnotic state, or to reduce aggression, or as an analgesic.
  • Dutch patent application 70/07029 discloses a group of 2-(3-pyridyl)thiazolylacetic acid derivatives as having antiinflammatory activity.
  • the present invention provides a method of reducing anxiety in an animal subject. This is achieved by administering to an animal subject a therapeutically effective amount of a specified 4-aryl-2-( 3-pyridyl)thiazole or a pharmaceutically acceptable acid addition salt thereof.
  • thiazole compounds that are employed in this invention may be represented by the following formula:
  • thiazole compounds may also be employed in the form of their pharmaceutically acceptable acid addition salts, e.g. hydrochlorides, sulfates, hydrobromides, hydroiodides, sulfonates, and the like.
  • the amount of such thiazole that will be administered will be from about 0.1 to 300 mg/kg/day of body weight, preferably from about 50 to 200 mg/kg/day. In humans, the amount will, be from about 0.4 to 4 mg/kg/day.
  • the invention further provides new pharmaceutical compositions comprising one of the above specified 4- aryl-2-( 3-pyridyl)thiazoles.
  • compositions comprise, in combination, a therapeutically effective amount of such a thiazole and a pharmaceutically acceptable carrier or diluent therefor.
  • the composition in the case of a tablet, will comprise, in addition to the active ingredient, fillers, binders and diluents such as lactose, methylcellulose, talc, gum tragacanth, gum acacia, agar, polyvinylpyrrolidone, stearic acid and corn starch.
  • a filler such as sodium carboxymethylcellulose and/or a syrup, e.g., a glycerine based syrup.
  • the composition will comprise the active ingredient and a suitable liquid solvent or dispersant such as a saline solution.
  • R 18 A preferred thiazole compound is N,N-dimethyl-4- phenyl-2-(3-pyridyl)-5-thiazolecarboxamide hydrochloride which is represented by the following formula:
  • the compounds of the present invention can be prepared by well known methods of thiazole synthesis such as the syntheses described in the application of Harrison et a1. mentioned above as well as in our previously filed application Ser. No. 264,817.
  • the compounds listed in Table 1 below were prepared indirectly from 4-phenyl-2-(3-pyridyl)- S-thiazolecarboxylic acid as described in our application Ser. No. 264,817, filed June 21, 1972.
  • hydrochloride was studied in the Neuropharmacological Profile [see Samuel Irwin, Science 136, 123 1962)], which is a standardized multidimensional observation technique used on mice to grade symptomatology and acute toxicity relative to dosage.
  • the hydrochloride was found to be a central nervous system depressant possessing anti-anxiety properties. Additionally, it possesses hypnotic, anti-aggressive, and analgesic properties. It is active orally in mice and ratsand in these species has a therapeutic index with respect to hypnotic activity [ratio of mean lethal dose (LD to mean effective dose (ED or, in this particular case, mean hypnotic dose (HD of approximately 3.
  • hydrochloride ferred to as the hydrochloride
  • NEUROPHARMACOLOGICAL PROFlLE served at the 300 mg/kg does level. Similar effects were.
  • HYPNOTlC ACTIVITY Since loss of righting reflex was observed in the neuropharmacological profile assay, it was desirable to determine the effective median dose for the induction of the loss of righting reflex (HDso).
  • the hydrochloride was administered orally to mice in a dose range of 100 400 mg/kg.
  • the calculated median hypnotic dose was 212.5 mg/kg, with 95% confidence limits of 150.5 335.5 mg/kg.
  • the onset of the loss of righting reflex at 200 mg/kg dose level was less than two minutes and had a mean duration of 60 minutes. Similar studies were preformed in rats, with the hydrochloride being administered orally in a dose range of 200 300 mg/kg.
  • the median hypnotic dose was calculated to be 249.5 mg/kg, with 95% confidence limits of 217.0 286.5 mg/kg. At this dose level, induction time for sleep was approximately 18 minutes and the loss of righting reflex persisted for approximately minutes. No deaths occurred in the mice or rats tested at the doses which approximated the effective median doses.
  • NTD NEUROTOXICITY
  • Srpm rotating wooden rod
  • Chlorpromazine and chlordiazepoxide each produced considerably more neurotoxic signs and symptoms than were observed when using the hydrochloride.
  • MAXIMAL ELECTROSHOCK SElZURES (MES Groups of 10 mice were injected i.p. with a vehicle and the test drug and placed in individual Plexiglas squares. Thirty minutes after i.p. injection, each mouse was administered an electric shock transcorneally at SOmA intensity, 0.2 seconds duration (Swinyard, et al., J. Pharmacol. Exptl. Tlzer. 106: 319, 1952). The criterion for activity is protection against tonic extension of the hind limbs. The dose necessary to protect 50% of the mice (MES was determined. The following results were obtained.
  • the hydrochloride is effective in protecting against maximal electroshock seizures.
  • chlordiazepoxide is four to five times more potent.
  • PENTYLENETETRAZOL SElZURES (MET TABLE V Pentylenetetrazol Seizures Agent 1.
  • P. MET, mg/kg The hydrochloride 66.0 (46.294.1 Convulsions 43.2 (29.064.3) for death Chlorpromazine Inactive 100 mg/kg) 7.1 (5.6- 90) Convulsions Chlordiazepoxide 2.6 (2.2-3.1) for death The hydrochloride antagonizes the convulsions induced by pentylenetetrazol. However, it is less potent than Chlordiazepoxide.
  • THIOSEMICARBAZIDE CON VULSIONS Seizures were produced in mice by the administration of 20 mg/kg i.p. of thiosemicarbazide (TSC). Thirty minutes later, the hydrochloride was given at 100 and 200 mg/kg i.p. Four hours later, following TSC administration, the hydrochloride had not protected.
  • TSC thiosemicarbazide
  • mice from convulsions and death.
  • the hydrochloride was studied for analgesic effect using the Haffner Tail-Pinch method. Mice were preselected for a positive reaction to the noxious stimulus of a continuous tail pinch. Groups of 10 mice each were injected with the hydrochloride i.p. at 50, 75, 100, 150, and 200 mg/kg. Control groups were injected with vehicle and evaluated simultaneously with the experimental groups. Thirty minutes later the tail pinch was applied for 30 seconds and the number of mice responding to the noxious stimulus was recorded. The hydrochloride was active in this assay and the median effective dose was calculated to be 100 mg/kg with 95% confidence limits of 79.5 to 126.0 mg/kg.
  • DIHYDROXYPHENYLALANINE FIGHTING TEST It is well known that when monoamine oxidase (MAO) inhibitors are administered prior to the administration of dl-DOPA, which is a noradrenaline precursor, convulsions or excitation occur. In this study, the MAO inhibitor pargyline mg/kg) was given 1, 2 and 4 hours prior to administering 200 mg/kg of dLDOPA. Results of this experiement are manifested by excitation, salivation, jumping, and fighting. When the hydro- CARDIOVASCULAR ACTIVITY The hydrochloride was studied in the pentobarbitalized dog for its possible effects on blood pressure, electrocardiogram, and respiration.
  • MAO monoamine oxidase
  • the hydrochloride was administered at 1 mg/kg iv. and then sequentially at 5 mg/kg for a total accumulative dose of 26 mg/kg.
  • the hydrochloride had no consistent effect on blood pressure, respiration or electrocardiogram up to and in-
  • parenterally administering the compounds or I compositions use may be made of a parenteral solution or suspension of the compounds in a suitable solvent or suspension medium.
  • the compounds and compositions of the present invention may also be administered rectally in the form of a suppository comprising an effective amount of the desired compound and a suitable vehicle such as petroleum jelly.
  • compositions according to the invention are specific formulations of compositions according to the invention:
  • EXAMPLE 1 Tablets may be prepared by the: compression of a wet cluding 25 mg/kg. There were transient decreases in granulation comammg the followmg: both systolic and diastolic blood pressures and in respiratory tidal volume, but these were associated with the lngmdiems In each injections and recovered to control levels several min- N.N dimethyl-4 phenyl-2-(3-pyridyl)-5- 25 mg. i F mlecnon thiazolecarboxiimide hydrochloride P vin 1 no id e 6 TOXICITY 13508! W 15 $5. Al h 1, 3A, 200 f l I.
  • Table Vll gives the results of five-day lethality studies 21 acid pm) 3 [2 following single injections of drug. All values presented Talc 4 s- Corn starch 15 mg. represent tests conducted when animals were housed 25 Dosage; 1 table, 3 time day 10 per cage. The hydrochloride was compared with chlorpromazine and chlordiazepoxide. In these and all the preceding calculations, the method of Litchfield EXAMPLE 2 and Wilcoxon (J. Pharmacol. Expt. Ther. 96: 99, 1949) t was used to estimate effective (ED or lethal (LD A q q Suspenslon f Oral admmlstl'atlon y be re ared in the followm formulation: dose. n P P 8 TABLE VII LD,,,, (95% Confidence Limits) mg/kg MICE RATS Agent I.P. P.O. P.O.
  • the compounds of the present invention may be administered to an animal subject in any of a 5 number of forms and via any of several routes.
  • the compounds or compositions thereof may be orally administered in the fonn of tablets, pills or capsules, or in the form of a solution or liquid suspension. They may also be administered in the form of a parenteral suspension or solution.
  • the compounds or compositions thereof may also be administered rectally, in the form of a suppository.
  • the compounds or compositions When orally administering the compounds or compositions, use can be made of a tablet, pill or capsule consisting entirely of one of the desired compounds, although ordinarily a composition comprising an effective amount of the compound and varying amounts of one or more physiologically inert materials such as carriers, vehicles, binders and the like will be used. Additionally, the compounds may be orally administered in the form of a suspension thereof in a suitable vehicle such as a syrup.
  • DFC Dry filled capsules
  • a parenteral suspension for intr'a-muscular administration may be prepared in the following formulation:
  • a suppository capsule may be formulated as below.
  • Dosage l suppository every 3 to 4 hours.
  • a method of reducing anxiety in an animal subject comprising administering to an animal subject characterized by the exhibition of anxiety a therapeutically effective amount of a thiazole com- P n q ttts o mqlaa wherein R is a n or a pharmaceutically acceptable acid addition salt thereof.
  • said orally administrable dosage form is a pill, tablet or capsule.
  • a pharmaceutical preparation in dosage unit form adapted for administration to obtain an antianxiety behavior effect comprising an anti-anxietyeffective non-toxic amount within the range from about 0.1 to about 300 mg./kg. of body weight of a compound of the formula:
  • composition of claim 17, wherein said suspension or solution comprises about 5 mg of said compound per cc.
  • composition of claim 13 in a parenterally administrable dosage form.
  • composition of claim 19, wherein said parenterally administrable dosage form comprises about mg of said compound per cc of suspension or solution.
  • composition of claim 13 in a rectally administrable dosage form.
  • composition of claim 22, wherein said suppository contains about 25 to 50 mg of said thiazole compound.
  • composition of claim 13, wherein said thiazole compound is N,N-dimethyl-4-phenyl-2-(3- pyridyl )-5-thiazolecarboxamide hydrochloride.
  • a method of inducing hypnosis in an animal subject comprising administering to an animal subject capable of undergoing hypnosis a therapeutically effective amount of N,N-dimethyl-4-phenyl-2- (3-pyridyl )-5-thiazolecarboxamide hydrochloride.
  • a pharmaceutical preparation in dosage unit form adapted for administration to obtain a hypnotic effect comprising a hypnotic effective non-toxic amount within the range from about 0.1 to about 300 mg./kg. of body weight of N,N-dimethyl-4-phenyl-2-( 3- pyridyl)-5-thiazolecarboxamide hydrochloride in combination with a physiologically acceptable carrier or diluent therefor.
  • a method of relieving pain in an animal subject comprising administering to an animal subject characterized by suffering from pain a therapeutically effective amount of N.N-dimethyl-4-phenyl- 2-( 3-pyridyl )-5-thiazolecarboxamide hydrochloride.
  • a pharmaceutical preparation in dosage unit form adapted for administration to obtain an analgesic effect comprising an analgesic effective non-toxic amount within the range from about 0.1 to about 300 mg./kg. of body weight of N,N-dimethyl-4-phenyl-2-( 3- pyridyl)-5-thiazolecarboxamide hydrochloride in combination with a physiologically acceptable carrier or diluent therefor.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US00295501A 1972-10-06 1972-10-06 Pharmaceutical compositions containing a4-aryl-2-(3-pyridyl)thiazole and methods of using same Expired - Lifetime US3821384A (en)

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US00295501A US3821384A (en) 1972-10-06 1972-10-06 Pharmaceutical compositions containing a4-aryl-2-(3-pyridyl)thiazole and methods of using same
DE19732350222 DE2350222A1 (de) 1972-10-06 1973-10-05 Pharmazeutische mittel, die ein 4-aryl-2-(3-pyridyl)-thiazol enthalten, und ihre anwendung
GB4654973A GB1451212A (en) 1972-10-06 1973-10-05 Pharmaceutical compositions containing a 4-aryl-2-3-pyridyl- thiazole and methods of using same
FR7335757A FR2208660B1 (enrdf_load_stackoverflow) 1972-10-06 1973-10-05

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US00295501A US3821384A (en) 1972-10-06 1972-10-06 Pharmaceutical compositions containing a4-aryl-2-(3-pyridyl)thiazole and methods of using same

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GB (1) GB1451212A (enrdf_load_stackoverflow)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4571402A (en) * 1982-06-22 1986-02-18 Schering Corporation Anti-bronchoconstriction 2-(4'-pyridinyl)-thiazole derivatives, composition, and method of use therefor
US4746669A (en) * 1985-12-23 1988-05-24 Merck & Co., Inc. Substituted thiazoles as immunoregulants
EP1348706A4 (en) * 2000-12-08 2005-08-10 Takeda Pharmaceutical SUBSTITUTED THIAZOLE DERIVATIVES CARRYING 3-PYRIDYL GROUPS, PROCESS FOR THEIR PRODUCTION AND USE THEREOF
US8765746B2 (en) 2010-10-13 2014-07-01 Millennium Pharmaceuticals, Inc. Heteroaryls and uses thereof
US8796271B2 (en) 2010-08-11 2014-08-05 Millennium Pharmaceuticals, Inc. Heteroaryls and uses thereof
US8796314B2 (en) 2009-01-30 2014-08-05 Millennium Pharmaceuticals, Inc. Heteroaryls and uses thereof
WO2014160197A1 (en) * 2013-03-13 2014-10-02 Musc Foundation For Research Development Thiazole compounds, compositions and methods for treatment of degenerative diseases and disorders
US8859768B2 (en) 2010-08-11 2014-10-14 Millennium Pharmaceuticals, Inc. Heteroaryls and uses thereof
US9029411B2 (en) 2008-01-25 2015-05-12 Millennium Pharmaceuticals, Inc. Thiophenes and uses thereof
US9062038B2 (en) 2010-08-11 2015-06-23 Millennium Pharmaceuticals, Inc. Heteroaryls and uses thereof
US9090601B2 (en) 2009-01-30 2015-07-28 Millennium Pharmaceuticals, Inc. Thiazole derivatives
US9139589B2 (en) 2009-01-30 2015-09-22 Millennium Pharmaceuticals, Inc. Heteroaryls and uses thereof

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3705153A (en) * 1969-05-14 1972-12-05 Sumitomo Chemical Co Novel thiazolyacetic acids and salts thereof

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4571402A (en) * 1982-06-22 1986-02-18 Schering Corporation Anti-bronchoconstriction 2-(4'-pyridinyl)-thiazole derivatives, composition, and method of use therefor
US4746669A (en) * 1985-12-23 1988-05-24 Merck & Co., Inc. Substituted thiazoles as immunoregulants
EP1348706A4 (en) * 2000-12-08 2005-08-10 Takeda Pharmaceutical SUBSTITUTED THIAZOLE DERIVATIVES CARRYING 3-PYRIDYL GROUPS, PROCESS FOR THEIR PRODUCTION AND USE THEREOF
US7067537B2 (en) 2000-12-08 2006-06-27 Takeda Pharmaceutical Company Limited Substituted thiazole derivatives bearing 3-pyridyl groups, process for preparing the same and use thereof
US9029411B2 (en) 2008-01-25 2015-05-12 Millennium Pharmaceuticals, Inc. Thiophenes and uses thereof
US9139589B2 (en) 2009-01-30 2015-09-22 Millennium Pharmaceuticals, Inc. Heteroaryls and uses thereof
US9090601B2 (en) 2009-01-30 2015-07-28 Millennium Pharmaceuticals, Inc. Thiazole derivatives
US8796314B2 (en) 2009-01-30 2014-08-05 Millennium Pharmaceuticals, Inc. Heteroaryls and uses thereof
US8796268B2 (en) 2010-08-11 2014-08-05 Millennium Pharmaceuticals, Inc. Heteroaryls and uses thereof
US8859768B2 (en) 2010-08-11 2014-10-14 Millennium Pharmaceuticals, Inc. Heteroaryls and uses thereof
US9062038B2 (en) 2010-08-11 2015-06-23 Millennium Pharmaceuticals, Inc. Heteroaryls and uses thereof
US8796271B2 (en) 2010-08-11 2014-08-05 Millennium Pharmaceuticals, Inc. Heteroaryls and uses thereof
US8765746B2 (en) 2010-10-13 2014-07-01 Millennium Pharmaceuticals, Inc. Heteroaryls and uses thereof
WO2014160197A1 (en) * 2013-03-13 2014-10-02 Musc Foundation For Research Development Thiazole compounds, compositions and methods for treatment of degenerative diseases and disorders
US9850218B2 (en) 2013-03-13 2017-12-26 Musc Foundation For Research Development Thiazole compounds, compositions and methods for treatment of degenerative diseases and disorders

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FR2208660B1 (enrdf_load_stackoverflow) 1976-07-02
DE2350222A1 (de) 1974-04-18
GB1451212A (en) 1976-09-29
FR2208660A1 (enrdf_load_stackoverflow) 1974-06-28

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